In utero alcohol exposure, epigenetic changes, and their consequences.

Ungerer M, Knezovich J, Ramsay M - Alcohol Res (2013)

Bottom Line:
The molecular mechanisms and processes underlying the teratogenic effects of alcohol exposure remain poorly understood and are complex, because the specific effects depend on the timing, amount, and duration of exposure as well as genetic susceptibility.These epigenetic effects are difficult to study, however, because they often are cell-type specific and transient in nature.Although recent studies using these models have yielded some insight into epigenetic mechanisms affecting brain development, they have generated more questions than they have provided definitive answers.

Affiliation: Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, National Health Laboratory, Service, Johannesburg, South Africa.

ABSTRACTExposure to alcohol has serious consequences for the developing fetus, leading to a range of conditions collectively known as fetal alcohol spectrum disorders (FASD). Most importantly, alcohol exposure affects the development of the brain during critical periods of differentiation and growth, leading to cognitive and behavioral deficits. The molecular mechanisms and processes underlying the teratogenic effects of alcohol exposure remain poorly understood and are complex, because the specific effects depend on the timing, amount, and duration of exposure as well as genetic susceptibility. Accumulating evidence from studies on DNA methylation and histone modification that affect chromatin structure, as well as on the role of microRNAs in regulating mRNA levels supports the contribution of epigenetic mechanisms to the development of FASD. These epigenetic effects are difficult to study, however, because they often are cell-type specific and transient in nature. Rodent models play an important role in FASD research. Although recent studies using these models have yielded some insight into epigenetic mechanisms affecting brain development, they have generated more questions than they have provided definitive answers. Researchers are just beginning to explore the intertwined roles of different epigenetic mechanisms in neurogenesis and how this process is affected by exposure to alcohol, causing FASD.

f2-arcr-35-1-37: Epigenetic contributions to FASD. Following conception, a complex orchestration of epigenetic mechanisms ensures normal cellular differentiation and embryonic development (green horizontal arrow). These mechanisms include DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) to modulate gene expression in a specified temporal and spatial manner. Alcohol exposure in utero (red downward arrow) has been shown to alter these epigenetic modulators, which may consequently dysregulate gene expression patterns as indicated by the study findings listed and affect normal embryonic development and phenotype outcome. By these mechanisms, alcohol-induced epigenetic aberrations may contribute to the etiology of fetal alcohol spectrum disorders (FASD).

Mentions:
Evidence is rapidly accumulating in support of an epigenetic etiology in the development of FASD (figure 2). All three types of epigenetic modulators—DNA methylation, histone modifications and regulation by ncRNAs—are perturbed by ethanol exposure. These ethanol-related changes can affect gene expression of critical developmental genes and pathways, impacting cell proliferation and differentiation.

f2-arcr-35-1-37: Epigenetic contributions to FASD. Following conception, a complex orchestration of epigenetic mechanisms ensures normal cellular differentiation and embryonic development (green horizontal arrow). These mechanisms include DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) to modulate gene expression in a specified temporal and spatial manner. Alcohol exposure in utero (red downward arrow) has been shown to alter these epigenetic modulators, which may consequently dysregulate gene expression patterns as indicated by the study findings listed and affect normal embryonic development and phenotype outcome. By these mechanisms, alcohol-induced epigenetic aberrations may contribute to the etiology of fetal alcohol spectrum disorders (FASD).

Mentions:
Evidence is rapidly accumulating in support of an epigenetic etiology in the development of FASD (figure 2). All three types of epigenetic modulators—DNA methylation, histone modifications and regulation by ncRNAs—are perturbed by ethanol exposure. These ethanol-related changes can affect gene expression of critical developmental genes and pathways, impacting cell proliferation and differentiation.

Bottom Line:
The molecular mechanisms and processes underlying the teratogenic effects of alcohol exposure remain poorly understood and are complex, because the specific effects depend on the timing, amount, and duration of exposure as well as genetic susceptibility.These epigenetic effects are difficult to study, however, because they often are cell-type specific and transient in nature.Although recent studies using these models have yielded some insight into epigenetic mechanisms affecting brain development, they have generated more questions than they have provided definitive answers.

Affiliation:
Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, National Health Laboratory, Service, Johannesburg, South Africa.

ABSTRACTExposure to alcohol has serious consequences for the developing fetus, leading to a range of conditions collectively known as fetal alcohol spectrum disorders (FASD). Most importantly, alcohol exposure affects the development of the brain during critical periods of differentiation and growth, leading to cognitive and behavioral deficits. The molecular mechanisms and processes underlying the teratogenic effects of alcohol exposure remain poorly understood and are complex, because the specific effects depend on the timing, amount, and duration of exposure as well as genetic susceptibility. Accumulating evidence from studies on DNA methylation and histone modification that affect chromatin structure, as well as on the role of microRNAs in regulating mRNA levels supports the contribution of epigenetic mechanisms to the development of FASD. These epigenetic effects are difficult to study, however, because they often are cell-type specific and transient in nature. Rodent models play an important role in FASD research. Although recent studies using these models have yielded some insight into epigenetic mechanisms affecting brain development, they have generated more questions than they have provided definitive answers. Researchers are just beginning to explore the intertwined roles of different epigenetic mechanisms in neurogenesis and how this process is affected by exposure to alcohol, causing FASD.